We have defined the molecular mechanisms whereby interactions of multiple myeloma (MM) cells with BM stromal cells (BMSCs) mediate growth, survival, and drug resistance in the BM milieu using in vitro and in vivo models. We have then validated novel therapeutics targeting the MM cell and its BM microenvironment (bortezomib, lenalidomide and combinations thereof), and rapidly translated these agents from bench to bedside and FDA approval. The current proposal will further define the molecular, functional, and therapeutic relevance of interactions of MM cells with accessory cells in the BM milieu. Our central hypothesis is that the interaction between MM cells and their surrounding accessory cells in the BM microenvironment is a bidirectional one, whereby MM cells prime the accessory cells to function as more potent inducers of MM cell proliferation, survival, and drug resistance. To address this hypothesis, we will characterize the molecular and functional impact of MM cells on BMSCs as accessory cells in the BM microenvironment (Specific Aim 1); define the role of MM-induced myeloid-derived suppressor cells (MDSCs) as candidate accessory cells directly supporting proliferation and drug resistance of MM cells in the BM (Specific Aim 2); and define the impact of MM cells on accessory cells in vivo and its therapeutic implications. Our studies will provide the framework for a new treatment paradigm, whereby the mechanism(s) of BM accessory cell priming by MM cells constitute bona fide target(s) for therapeutic interventions to overcome drug resistance and improve patient outcome.